What are the Beta-sarcoglycanopathy (LGMD2E  LGMDR4) and other lgmd


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LIMB-GIRDLE MUSCULAR DYSTROPHIES   (LGMD)


Disease definition
Limb-girdle muscular dystrophy (LGMD) is a heterogeneous group of muscular dystrophies characterized by proximal weakness affecting the pelvic and shoulder girdles. Cardiac and respiratory impairment may be observed in certain forms of LGMD.


Epidemiology
The estimated prevalence for all forms of LGMD ranges from 1/44,000 to 1/123,000.


Clinical description
LGMD ranges from severe forms with onset in the first decade and rapid progression (resembling Duchenne muscular dystrophy) to milder forms with late onset and slower progression (similar to Becker muscular dystrophy). LGMD is characterized by weakness and wasting predominantly of the limb musculature (proximal greater than distal). The initial presentations are usually weakness of the hip and proximal leg muscles. Affected individuals usually have normal early motor and intellectual milestones and show a positive Gowers' sign. Cardiac involvement in the form of dilated or hypertrophic cardiomyopathy and dysrhythmias are present in LGMD 2C-F, 2I, 2W, 2X, 1B, and 1E. At some stage, when upper arm muscles are involved, all subtypes may also have respiratory muscle weakness with nocturnal hypoventilation, in particular type 2I where it is noted from an earlier stage. Additional clinical features include a waddling gait, muscle pain during exercise, hypertrophy of the deltoids and quadriceps, and muscle wasting, affecting either the pelvis and/or shoulder girdle. The facial muscles are usually spared or involved only minimally.


Etiology
LGMD is caused by mutations in more than 30 genes which encode numerous components of the myofiber, contractile apparatus, nuclear lamina, sarcolemma or the cytoplasm.


Diagnostic methods
Diagnosis of LGMD involves physical examination and muscle biopsy, which reveals fiber size variation including (non specific) fiber hypertrophy, scattered degenerating and regenerating muscle fibers, and a mild increase in perimysial tissue. Serum creatine-kinase can be normal or mildly to grossly elevated.
Diagnosis of a specific LGMD subtype can be achieved by biochemical protein testing performed on muscle biopsies, followed by confirmation with genetic testing. Genetic testing, using panels, is becoming more readily available and can confirm diagnosis.


Differential diagnosis
The differential diagnosis of LGMD includes facioscapulohumeral muscular dystrophy, Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, polymyositis, myotonic, myofibrillar, distal and metabolic myopathy, collagen 6-related disorders and dermatomyosistis.
Antenatal diagnosis Prenatal diagnosis is available when a causative gene in a family is known.


Genetic counseling
There are at least 30 different genetic forms of LGMD, among which the type 1 LGMDs (LGMD1) are inherited in an autosomal dominant manner and the type 2 LGMDs (LGMD2) are inherited in an autosomal recessive manner. Genetic counseling should be offered to families according to the mode of inheritance.


Management and treatment

Treatment of LGMD remains palliative and supportive and includes weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and prevent contractures, use of mechanical aids to help ambulation and mobility, surgical intervention for orthopedic complications, use of respiratory aids when indicated, monitoring for cardiomyopathy in LGMD types with cardiac involvement, and social as well as emotional support and stimulation.


Prognosis
The clinical course of LGMD is typically progressive, although it is highly variable and is dependent on the severity of the individual genetic mutation. In most childhood onset forms of LGMD (in particular the rapidly progressive forms), ambulation is achieved but is invariably lost in later years. In other forms of LGMD, ambulation can be maintained and wheelchair assistance needed only later in life.


Overview of old and new names of LGMD-subtypes:

All LGMD-subtypes

 

the beta-sarcoglycanopathy - lgmd2e or lgmdr4

 

It has been shown that SGCB expresses a 43-kD component of the dystrophin-glycoprotein complex and is involved in a form of LGMD, designated LGMD2E or LGMDR4 (Bonnemann et al 1995; Lim et al 1995). Symptoms of the disease very greatly from person to person, even among people in the same family.

Symptoms

LGMD2E or LGMDR4 is often associated with severe symptoms that can be fatal by the late teens, although some people with the disease have a mild course or are nearly asymptomatic. People with LGMD2E (or LGMDR4) commonly develop symptoms before the age of 10, although in some cases, symptoms do not appear until later. In people with LGMD2E (or LGMDR4), the muscles of the hip, shoulder, and abdomen progressively weaken, often to a point where a wheelchair becomes necessary. This typically happens between the ages of 10 and 15. In people with LGMD2E (or LGMDR4), muscles attached to the scapula, a bone that connects the arm with the collar bone, do not work properly, causing a wing-like shape to the upper back. The calf muscles are often enlarged as well, a symptom known as calf hypertrophy. A minority of people with LGMD2E (about 20%) experience a weakening of the heart muscles (Fanin et al 2003; Barresi et al. 2000). However, involvement of the heart muscles is less common in type 2E or R4 than in other forms of limb girdle muscular dystrophy.

Mutations

Functional studies have shown that beta-sarcoglycan co-localizes with the DGC at the sarcolemma and is predominantly expressed in muscle. The SGCB gene contains 6 exons and spans a relatively short genomic DNA regions of about 13.5 kb. Different type of mutation have been identified and mapped in the SGCB gene, and correlate with LGMD2E or LGMDR4. Most of them are point mutations including: missense mutations resulting in amino acid substitutions; nonsense mutations that cause premature stop of the protein synthesis; frameshift mutations due to single base insertions or to short insertions/deletions generating out of frame non functional proteins (Bonnemann et al 1998; Bonnemann et al 1996). Importantly, as in the case of other sarcoglycans of the DGC, impairment in the expression of one component can affect expression and stability of the other sarcoglycans. Western blot analyses have shown that patients with reduced expression of beta sarcoglycan often display reduction or even total absence of the other sarcoglycans (Fanin and Angelini 2002). This suggests that the stoichiometry of the complex is finely regulated and tightly controlled.

Possible gene therapy strategies

This aspect is extremely important and has strong implications in the design of possible gene therapy strategies. Simplistically, the endogenous defect may be correct by expressing the wild type protein in the LGMD2E (or LGMDR4) muscle cells. However, due to the complex control of the stoichiometry of the DGC complex, the simple overexpression of the SGCB protein may be inadequate to re-establish a functional DGC. An excess of the SGCB protein may lead to formation of incomplete DGC that most likely will generate non-functional complexes. To avoid this kind of problems, the SGCB gene therapy construct should retain the tight expression control of the endogenous gene. To achieve this objective it is, however, crucial to identify the cis and trans regulatory elements that coordinate such control. As far as we know, very little information, if none, has been accrued about the transcription and post-transcriptional regulation of this gene.

More

Then LGMD2E or LGMDR4 is transmitted as an autosomal recessive form and is caused by mutation in the gene encoding beta-sarcoglycan that is located on chromosome 4q12. LGMD2E (or LGMDR4) is characterized by scapular winging and calf hypertrophy. Age of onset is usually between 2 years and the mid-teenage years. Cardiac involvement occurs in about 20% of cases. Serum creatine kinase (CK) activity is always elevated. The overall prevalence of primary sarcoglycanopathies in northeast Italy was estimated to be 1/200,000. No specific treatment is known and many patients receive physical therapy to prevent worsening of contractures. *Author: Dr A. van der Kooi (October 2004)*.

Steroid therapy

In Italy some children follow a steroid therapy according to a protocol provided for Duchenne muscular dystrophy. Deflazocort in a low dosage is used in the pharmaceutical form of Deflan and Flantadin. Vitamin D (Didrogyl) and calcium (Calcium Sandoz) are also administered. Patients have the right to have medicine exemption, the specialist has to fill in the form for medicine prescript related to rare diseases.

Gene structure

Distinguishing mark of this disease is the fact that it is caused by a very small gene, made up of only 6 exons. Other sarcoglycanopathies have bigger genes too :

number of patients

For more information LOVD (Leiden Open Variation Database)

 

Genomic organization of the beta-sarcoglycan gene.

Filled in boxes signify coding regions, open boxes refer to untranslated regions.

Exons are designatedE1–E6. Intron numbering follows exon numbering.

Approximate intron sizes are indicated in kilobases (kb).

 

For this reason, the gene of beta-sarcoglycanopathy is particularly suitable for the application of gene therapy.

Statistics

From the data collected in the Leiden database LOVD, people suffering from beta-sarcoglycanopathy are estimated at 355 worldwide (as of August 30, 2011). Of these 130 have a mutation on the exon 1 and 133 on the 3 one. The mutations are less frequent on other exons. In Italy there are 45 cases reported in the north-east of the country, of which 23 have the exact same mutation on the exon 3. The data on the spatial distribution and type of mutation are shown in detail in the statistics.

Distribution of this disease in each country.

Germany has the biggest number of cases: 123.

Italy follows with 45 cases,  gathered around the north-east area of the country.

(Updates August 30th  2011)

 

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